This proposal seeks to develop a genome-wide in vivo approach to define the suite of regulatory interactions controlling mRNA translation in the nervous system. A fundamental property of the brain is that perceptual experiences drive modifications in number and strength of synaptic connections among neurons. These synapse modifications, which are thought to be neural correlates of memory and cognition, require synthesis of specific proteins at individual synaptic sites in response to neural activity. The mechanisms governing this local synthesis of synaptic proteins are poorly understood, but its disruption can have severe consequences. This proposal describes a method that will provide individual genetic reporters of neural translation for each gene, and will identify the suite of regulatory mechanisms. The approach involves several steps. First is a method to create in vivo reporters of translation for each gene. Second is a high-throughput strategy to identify the set of genes whose translation is governed by a particular regulator. As a proof of principle, we will define the targets of 5 key translational regulators, including Fragile-X protein. Fragile-X is the most common inherited form of mental retardation. This proposal also will generate a resource that will empower the research community to identify the set of targets for any translational regulator. Our method takes advantage of the exceptional genetic manipulability of the Drosophila model system. The high degree of conservation of gene regulatory mechanisms and function ensures that much of what we learn will be transferable to humans. PUBLIC HEALTH RELEVANCE: A fundamental property of the brain is that our experiences cause modifications in number and strength of the connections among neurons. These changes, which are thought to underlie memory and cognition, require the precise control of the synthesis of specific proteins at the sites of these connections (1-5). The mechanisms governing this local synthesis of synaptic proteins are poorly understood, although we do know that disruption of this process has severe consequences. This defect is thought to be responsible for the Fragile-X syndrome. This proposal describes a method that can provide individual reporters of the regulation of protein synthesis for each gene in the genome, and can identify the regulatory mechanisms controlling each one.